Erythropoiesis: Heme and Bilirubin Metabolism
The liver is the primary erythropoietic organ of the fetus between
the 9th and 24th week of gestation. It continues to be a major site of hematopoiesis
until an infant is about 2 months of age. Recognizable hematopoietic cells normally
disappear from the liver as the bone marrow develops. With certain diseases, however,
they may persist (e.g., congenital hemolytic anemias) or reappear (e.g., bone marrow
failure or myeloproliferative disorders).
In healthy adults, the liver is responsible for about 20% of heme
production; bone marrow makes the rest. The two organs use nearly identical pathways
to synthesize heme, although the regulatory mechanisms differ slightly.[112]
[123]
[124]
[125]
[126]
The focus here is on the hepatocellular pathway.
Heme synthesis begins in mitochondria. In the first step, which is rate-limiting
in the synthesis of heme, 5-aminolevulinic acid (ALA) synthase condenses glycine
and succinyl-CoA, to produce ALA. Heme is the main (feedback) inhibitor of ALA synthase.
ALA diffuses from mitochondria into the cytoplasm, where ALA dehydratase links two
ALA molecules together to produce porphobilinogen (PBG). The linear arrangement
of PBG molecules by PBG deaminase yields hydroxymethylbilane (HMB). HMB is transformed
to uroporphyrinogen III, which is converted to coproporphyrinogen III. Mitochondria
take up coproporphyrinogen III and convert it to protoporphyrin IX through the actions
of coproporphyrinogen oxidase and protoporphyrin oxidase. In the final step of the
pathway, ferrochelatase adds ferrous iron to protoporphyrin IX, creating heme. In
other words, heme is a complex of ferrous iron and protoporphyrin IX. Subjecting
porphyrinogens to oxygen rapidly oxidizes them to matching porphyrins.
Porphyrias
Porphyrias are uncommon disorders of heme synthesis (porphyrin
metabolism). Usually, the disorder remains subclinical until an endogenous or exogenous
stress triggers a porphyric crisis.[127]
Clinical
features of acute porphyrias include recurrent, dramatic, and potentially fatal neurologic
reactions. Most patients develop abdominal pain (90%) and dark urine (80%). Neurotoxicity
may result from increased plasma and tissue levels of porphyrin precursors (particularly
ALA and PBG), which have chemical structures resembling the inhibitory neurotransmitter
γ-aminobutyric acid (GABA). The most common of the acute porphyrias is acute
intermittent porphyria (AIP). Its prevalence is about 1 in 10,000 in the general
population and may be as high as 1 in 500 among patients with psychiatric disorders.
Women are five times more likely than men to have AIP. Among the triggers of porphyric
crises are sex hormones, glucocorticoids, cigarette smoking, and medications,[112]
[128]
[129]
including
certain anesthetic agents (e.g., barbiturates, etomidate, enflurane, pentazocine).
[129]
Barbiturates and other inducers of cytochrome
P-450 (CYP) stimulate the synthesis of cytochrome protein; incorporating heme into
newly forming hemoproteins causes the intracellular heme concentration to decline.
[129]
[130]
[131]
[132]
The decrease in heme reduces the inhibitory
influence on ALA synthetase, which is rate-limiting, and thus porphyrin (heme) synthesis
speeds up.[133]
[134]
Hemoglobin Metabolism and Bilirubin
The metabolism of hemoglobin produces bilirubin.[112]
About 300 mg of bilirubin is formed daily, mostly from the destruction of senescent
erythrocytes by macrophages of the reticuloendothelial system. These macrophages
(mainly in the spleen, liver, and bone marrow) extract the protein portion of hemoglobin
and then catabolize heme in a two-step process. First, heme oxygenase cleaves the
porphyrin macrocycle of heme, in a reaction that consumes molecular oxygen and produces
carbon monoxide, ferrous iron, and a linear tetrapyrrole (biliverdin). Second, cytoplasmic
reductases rapidly convert biliverdin to bilirubin.[135]
The bilirubin is released into the bloodstream and binds tightly
to albumin. Hepatic parenchymal cells avidly extract protein-bound bilirubin and
conjugate it, using glucuronic acid and bilirubin UDP-glucuronosyltransferase. Hepatocytes
secrete bilirubin conjugates into the canalicular bile, which flows into the alimentary
tract. Most conjugated bilirubin undergoes intestinal excretion, with little returning
to the liver in the enterohepatic circulation. In healthy individuals, only a small
fraction of conjugated bilirubin enters the plasma by direct (from hepatic sinusoids)
or indirect (absorption from bile ducts or lymphatics) routes.[136]
