Heme metabolism.

 Heme from hemoglobin is metabolized to biliverdin by the heme oxygenase (HO) enzyme. Heme oxygenase enzyme activity is accounted for by two separate proteins: one is the constitutive heme oxygenase-2 (HO-2) found in neurons and vascular cells, and the other is the inducible heme oxygenase-1 (HO-1) protein that is induced in marcrophages and microglia and other cells. Biliverdin is metabolized to bilirubin via biliverdin reductase. Free radicals act on bilirubin, biliverdin, and possibly heme to produce BOXes. Iron released by metabolism of heme or breakdown of heme can be bound by ferritin intracellularly or transferrin extracellularly. Any free iron can interact with H2O2 to produce hydroxyl free radicals and oxidize bilirubin, biliverdin or heme.

INTRODUCTION

Bilirubin is the potentially toxic catabolic product of heme metabolism. Fortunately, there are elaborate physiologic mechanisms for its detoxification and disposition. Understanding these mechanisms is necessary for interpretation of the clinical significance of high serum bilirubin concentrations. Furthermore, because bilirubin shares its metabolic pathway with various other sparingly water soluble substances that are excreted in bile, understanding bilirubin metabolism also provides insight into the mechanisms of transport, detoxification, and elimination of many other organic anions.

An overview of the major aspects of bilirubin formation and disposition will be reviewed here. The settings in which bilirubin disposition is impaired will also be discussed briefly. Clinical aspects of serum bilirubin determination, the evaluation of patients with hyperbilirubinemia, and the classification of causes of jaundice are presented separately. 

FORMATION OF BILIRUBIN

Bilirubin is formed by breakdown of heme present in hemoglobin, myoglobin, cytochromes, catalase, peroxidase and tryptophan pyrrolase. Eighty percent of the daily bilirubin production (250 to 400 mg in adults) is derived from hemoglobin [1]; the remaining 20 percent being contributed by other hemoproteins and a rapidly turning-over small pool of free heme. Enhanced bilirubin formation is found in all conditions associated with increased red cell turnover such as intramedullary or intravascular hemolysis (eg, hemolytic, dyserythropoietic, and megaloblastic anemias).

Heme consists of a ring of four pyrroles joined by carbon bridges and a central iron atom (ferroprotoporphyrin IX). Bilirubin is generated by sequential catalytic degradation of heme mediated by two groups of enzymes:

Heme oxygenase

Biliverdin reductase